1. Field of the Invention
This invention relates to novel 1-thiogalactose derivatives which inhibit binding of heat labile toxin (LT) and/or chlorea toxin (CT) to cell surface receptors either in vitro or in vivo. Additionally, the compounds of this invention inhibit binding of enterovirulent microorganisms (e.g., bacteria, virus, fungi, and the like) such as Vibrio cholerae and enterotoxigenic strains of Escherichia coli to cell surface receptors.
2. References
The following publications, patents and patent applications are cited in this application as superscript numbers:
.sup.1 Spangler, B. D., "Structure and Function of Cholera Toxin and Related Escherichia coli Heat-Labile Enterotoxin", Microbiological Reviews, 56(4):622-647 (1992). PA1 .sup.2 Hol, W. G. J., et al., "Structure and Function of E. coli Heat-Labile Enterotoxin and Cholera Toxin B Pentamer", Bacterial Toxins and Virulence Factors in Disease, Ed. by J. Moss et al., Marcel Dekker, Inc. (1995). PA1 .sup.3 Williams (ed.), Synthesis of Optically Active .alpha.-Amino Acids, Pergamon Press (1989). PA1 .sup.4 Evans et al., J. Amer. Chem. Soc., 112:4011-4030 (1990). PA1 .sup.5 Pu et al., J. Amer. Chem. Soc., 56:1280-1283 (1991). PA1 .sup.6 Williams et al., J. Amer. Chem. Soc., 113:9276-9286 (1991). PA1 .sup.7 Svennerholm, A-M. et al., Current Microbiology, 1:19-23 (1978). PA1 R.sup.2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic and thioalkoxyalkyl; PA1 R.sup.3 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic and thioalkoxyalkyl; wherein R.sup.1 and R.sup.2 or R.sup.1 and R.sup.3 or R.sup.2 and R.sup.3 can be joined, together with the carbon atoms to which R.sup.1 and/or R.sup.2 and/or R.sup.3 are attached, to form a cycloalkyl ring, a cycloalkenyl ring, or a heterocyclic ring; PA1 R.sup.4 is selected from the group consisting of --XR.sup.5, --XC(O)R.sup.6, --XC(O)X'R.sup.7 and --C(O)XR.sup.8 ; PA1 wherein X and X' are each independently selected from the group consisting of oxygen, sulfur and --NR.sup.9 --, wherein R.sup.9 is selected from the group consisting of hydrogen and alkyl; PA1 R.sup.5 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic and thioalkoxyalkyl, and when X is --NR.sup.9 --, then R.sup.9 together with X can form an amino acid; PA1 R.sup.6 is selected from the group consisting of alkyl, alkenyl, aralkyl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic and thioalkoxyalkyl; PA1 R.sup.7 is selected from the group consisting of alkyl, alkenyl, alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic and thioalkoxyalkyl; PA1 R.sup.8 is selected from the group consisting of alkyl, alkenyl, alkaryl, alkoxyalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic and thioalkoxyalkyl; and PA1 n is an integer equal to 0 or 1; PA1 when R.sup.1 and R.sup.2 are joined, together with the carbon atoms to which they are attached, to form a cyclohexyl ring, R.sup.4 is --XR.sup.5, X is oxygen and n is 0, then R.sup.5 is not hydrogen; PA1 when R.sup.1 and R.sup.2 are joined, together with the carbon atoms to which they are attached, to form a cyclohexyl ring, R.sup.4 is --XC(O)R.sup.6, X is --NH-- and n is 0, then R.sup.6 is not 2-carboxyphenyl; PA1 when R.sup.1 and R.sup.2 are joined, together with the carbon atoms to which they are attached, to form a cyclohexyl ring, R.sup.4 is --XR.sup.5, X is --NR.sup.9 -- and n is 0, then X and R.sup.5 together do not form the amino acid L-leucine; PA1 when R.sup.1 and R.sup.2 are joined, together with the carbon atoms to which R.sup.1, R.sup.2 and R.sup.3 are attached, to form a cyclopentyl or cycloheptyl ring, R.sup.3 is hydrogen, R.sup.4 is --XR.sup.5, X is oxygen and n is 1, then R.sup.5 is not hydrogen; PA1 when R.sup.1 and R.sup.2 are joined, together with the carbon atoms to which R.sup.1, R.sup.2 and R.sup.3 are attached, to form a cyclohexyl ring, R.sup.3 is hydrogen, R.sup.4 is --C(O)R.sup.6, X is --NH-- and n is 1, then R.sup.6 is not methyl.
All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
Toxins produced by bacteria and other organisms are known to cause a number of human diseases, including many diarrheal diseases. For example, heat-labile enterotoxin ("LT"), secreted by certain enterotoxigenic strains of Escherichia coli, has been identified as one of the causative agents of bacterial-induced traveller's diarrhea..sup.1 Additionally, cholera toxin ("CT"), produced by Vibrio cholerae, has been identified as the causative agent of the severe diarrheal disease, cholera..sup.1
Heat-labile enterotoxin and cholera toxin are known to bind to oligosaccharide receptors on host cells as an initial step in the pathological development of the associated disease condition..sup.2 Specifically, both LT and CT are known to bind to ganglioside G.sub.M1, a glycosphingolipid situated in the outer leaflet of the host cell membrane..sup.2 G.sub.M1 has a characteristic pentasaccharide structure, i.e., Gal(.beta.1.fwdarw.3)GalNAc(.beta.1.fwdarw.4){NeuAc(.alpha.2.fwdarw.3)}Gal (.beta.1.fwdarw.4)Glc, on its surface which serves as a receptor for LT and CT. LT is also known to bind to other gangliosides, such as ganglioside G.sub.D1b.
Additionally, enterovirulent microorganisms (e.g., bacteria, virus, fungi, and the like) such as Vibrio cholerae and enterotoxigenic strains of Escherichia coli can directly bind to cell surface receptors forming a colony at the point of attachment. Such binding is detrimental because it permits expressed toxin to immediately interact with the cell surface.
In order to treat or prevent bacterial-induced traveller's diarrhea and/or cholera, it would be highly desirable to be able to inhibit the binding of LT and/or CT to their corresponding cell surface receptors as well as the binding of Vibrio cholerae and enterotoxigenic strains of Escherichia coli can directly bind to cell surface receptors. The present invention provides novel 1-thiogalactose derivatives which effectively inhibit such binding.